Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification

Abstract

Genetic analysis in Caenorhabditis elegans has uncovered essential roles for DAF-16 in longevity, metabolism, and reproduction. The mammalian orthologs of DAF-16, the closely-related FOXO subclass of forkhead transcription factors (FKHR͞FOXO1, FKHRL1͞FOXO3a, and AFX͞FOXO4), also have important roles in cell cycle arrest, apoptosis and stress responses in vitro, but their in vivo physiological roles are largely unknown. To elucidate their role in normal development and physiology, we disrupted each of the Foxo genes in mice. Foxo1-null embryos died on embryonic day 10.5 as a consequence of incomplete vascular development. Foxo1-null embryonic and yolk sac vessels were not well developed at embryonic day 9.5, and Foxo1 expression was found in a variety of embryonic vessels, suggesting a crucial role of this transcription factor in vascular formation. On the other hand, both Foxo3a-and Foxo4-null mice were viable and grossly indistinguishable from their littermate controls, indicating dispensability of these two members of the Foxo transcription factor family for normal vascular development. Foxo3a-null females showed age-dependent infertility and had abnormal ovarian follicular development. In contrast, histological analyses of Foxo4-null mice did not identify any consistent abnormalities. These results demonstrate that the physiological roles of Foxo genes are functionally diverse in mammals.

Long live FOXO: unraveling the role of FOXO proteins in aging and longevity

“…FOXO6 is mainly expressed in the brain and has been shown to be regulated by distinct mechanisms. Interestingly, knockouts of single Foxo genes in mice present with very distinct outcomes: Foxo1 knockout mice die in utero due to defects in vasculature (Furuyama et al ., 2004; Hosaka et al ., 2004). Female Foxo3 knockout mice were found to be sterile due to global primordial follicle activation with subsequent oocyte exhaustion (Castrillon et al ., 2003; Hosaka et al ., 2004).…”

“…Interestingly, knockouts of single Foxo genes in mice present with very distinct outcomes: Foxo1 knockout mice die in utero due to defects in vasculature (Furuyama et al ., 2004; Hosaka et al ., 2004). Female Foxo3 knockout mice were found to be sterile due to global primordial follicle activation with subsequent oocyte exhaustion (Castrillon et al ., 2003; Hosaka et al ., 2004). In addition, depletion of Foxo3 resulted in deficient development of regulatory T cells with consequent organ inflammation by a mechanism also involving Foxo1 (Harada et al ., 2010; Kerdiles et al ., 2010).…”

Effect of forkhead box O1 (FOXO1) on beta cell development in the human fetal pancreas

“…Mouse embryos lacking FOXO1 demonstrate incomplete vascular development and do not survive beyond e10.5 [17]. Because of this early lethality, the role of FOXO1 during pancreatic organogenesis has not been thoroughly investigated.…”

Relative expression of genes encoding SMAD signal transduction factors in human granulosa cells is correlated with oocyte quality

“…Patient characteristics were as follows: age 35 ±4.04; fertilization rates 0.67±0.26. The number of oocytes retrieved was, as expected, found to correlate significantly with E2 levels (Fig.…”

“…Thus, understanding the mechanisms and pathways underlying fertility and fecundity remains of crucial importance. As the SMAD signal transduction proteins are known to mediate signaling by members of the TGF-β superfamily, which is involved in the control of normal folliculogenesis and ovulation [7,8], and they associate with members of the Forkhead family of transcription factors, the FOXO class [34], thought to play important roles in oocyte maturation, ovulation, and possibly luteinization [34][35][36][37][38][39], with expression in human granulosa cells [40], it is possible that SMAD expression levels may also affect ovarian folliculogenesis and fertility. Female Smad3 −/− mice exhibit impaired folliculogenesis and reduced fertility [28,30] and Smad4 ovarian-specific knockout mice exhibit multiple defects in folliculogenesis and decreased fertility over time [27].…”